RT Journal Article
SR Electronic
T1 Loss of CIC promotes mitotic dysregulation and chromosome segregation defects
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 533323
DO 10.1101/533323
A1 Suganthi Chittaranjan
A1 Jungeun Song
A1 Susanna Y. Chan
A1 Stephen Dongsoo Lee
A1 Shiekh Tanveer Ahmad
A1 William Brothers
A1 Richard D. Corbett
A1 Alessia Gagliardi
A1 Amy Lum
A1 Annie Moradian
A1 Stephen Pleasance
A1 Robin Coope
A1 J Gregory Cairncross
A1 Stephen Yip
A1 Emma Laks
A1 Samuel A.J.R. Aparicio
A1 Jennifer A. Chan
A1 Christopher S. Hughes
A1 Gregg B. Morin
A1 Veronique G. LeBlanc
A1 Marco A. Marra
YR 2019
UL http://biorxiv.org/content/early/2019/01/29/533323.abstract
AB Background CIC is a transcriptional repressor inactivated by loss-of-function mutations in several cancer types, including gliomas, lung cancers, and gastric adenocarcinomas. CIC alterations and/or loss of CIC activity have been associated with poorer outcomes and more aggressive phenotypes across cancer types, which is consistent with the notion that CIC functions as a tumour suppressor across a wide range of contexts.Results Using mammalian cells lacking functional CIC, we found that CIC deficiency was associated with chromosome segregation (CS) defects, resulting in chromosomal instability and aneuploidy. These CS defects were associated with transcriptional dysregulation of spindle assembly checkpoint and cell cycle regulators. We also identified novel CIC interacting proteins, including core members of the SWI/SNF complex, and showed that they cooperatively regulated the expression of genes involved in cell cycle regulation. Finally, we showed that loss of CIC and ARID1A cooperatively increased CS defects and reduced cell viability.Conclusions Our study ascribes a novel role to CIC as an important regulator of the cell cycle and demonstrates that loss of CIC can lead to chromosomal instability and aneuploidy in human and murine cells through defects in CS, providing insight into the underlying mechanisms of CIC’s increasingly apparent role as a “pan-cancer” tumour suppressor.